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Relationship between antiapoptotic molecules and metastatic potency and the involvement of DNA-dependent protein kinase in the chemosensitization of metastatic human cancer cells by epidermal growth factor receptor blockade.

Abstract
The failure to treat metastatic cancer with multidrug resistance is a major problem for successful cancer therapy, and the molecular basis for the association of metastatic phenotype with resistance to therapy is still unclear. In this study, we revealed that various metastatic cancer cells showed consistently higher levels of antiapoptotic proteins, including Bcl-2, nuclear factor-kappaB, MDM2, DNA-dependent protein kinase (DNA-PK), and epidermal growth factor receptor (EGFR), and lower levels of proapoptotic proteins, including Bax and p53 than low metastatic parental cells. This was followed by chemo- and radioresistance in metastatic cancer cells compared with their parental cells. EGFR and DNA-PK activity, which are known to be associated with chemo- and radioresistance, were demonstrated to be mutually regulated by each other. Treatment with PKI166, an EGFR inhibitor, suppressed etoposide-induced activation of DNA-PK in A375SM metastatic melanoma cells. In addition, PKI166 enhanced markedly the chemosensitivities of metastatic cancer cell sublines to various anticancer drugs in comparison with those of low metastatic cancer cells. These results suggest that the activities of DNA-PK and EGFR, which is positively correlated with each other, may contribute to metastatic phenotype as well as therapy resistance, and the EGFR inhibitor enhances the effect of anticancer drugs against therapy-resistant metastatic cancer cells via suppression of stress responses, including activation of DNA-PK.
AuthorsJee Hyun Um, Joong Keun Kwon, Chi-Dug Kang, Mi Ju Kim, Dong Sik Ju, Jae Ho Bae, Dong Wan Kim, Byung Seon Chung, Sun Hee Kim
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 311 Issue 3 Pg. 1062-70 (Dec 2004) ISSN: 0022-3565 [Print] United States
PMID15273254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • DNA-Binding Proteins
  • Indicators and Reagents
  • Nuclear Proteins
  • Pyrimidines
  • Pyrroles
  • Radiation-Sensitizing Agents
  • Etoposide
  • PKI 166
  • ErbB Receptors
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein Serine-Threonine Kinases
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Antineoplastic Agents, Phytogenic (pharmacology)
  • Apoptosis (drug effects, physiology)
  • Blotting, Western
  • Cell Line, Tumor
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins (metabolism)
  • Drug Synergism
  • Electrophoretic Mobility Shift Assay
  • ErbB Receptors (antagonists & inhibitors)
  • Etoposide (pharmacology)
  • Genes, MDR (genetics)
  • Humans
  • Indicators and Reagents
  • Melanoma (pathology)
  • Neoplasm Metastasis (drug therapy, physiopathology, radiotherapy)
  • Nuclear Proteins
  • Protein Serine-Threonine Kinases (metabolism)
  • Pyrimidines (pharmacology)
  • Pyrroles (pharmacology)
  • Radiation-Sensitizing Agents (pharmacology)
  • Rats

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